Salicylic acid salts of salmeterol

ABSTRACT

The present invention relates to new substituted salicylic acid salts of salmeterol, processes for preparing them and their use

RELATED APPLICATIONS

[0001] Benefit of U.S. Provisional Application Serial No. 60/386,172,filed on Jun. 5, 2002 is hereby claimed, and said application is hereinincorporated by reference in its entirety.

FIELD OF THE INVENTION

[0002] The present invention relates to new substituted salicylic acidsalts of salmeterol, processes for preparing them and their use aspharmaceutical compositions.

DETAILED DESCRIPTION OF THE INVENTION

[0003] The problem of the present invention is to prepare salts ofsalmeterol which are characterised by a high degree of localcompatibility, particularly when administered by inhalation.

[0004] This problem is solved with the substituted salicylic acid saltsof formula 1 shown below. Accordingly, the present invention relates tosalts of general formula 1

[0005] wherein

[0006] R¹ and R² which may be identical or different, denote hydrogen,C₁-C₄-alkyl, C₁-C₄-alkoxy, halogen, COOH, OH, —COOC₁-C₄-alkyl,—CO—C₁-C₄-alkyl, —NH₂, —NH(C₁-C₄-alkyl), —N(C₁-C₄-alkyl)₂, —SO₂—OH, —CF₃or phenyl;

[0007] R³ denotes hydrogen, C₁-C₄-alkyl, C₁-C₄-alkoxy, halogen, —CF₃ orphenyl, while the phenyl ring may optionally be mono-, di- ortrisubstituted by one, two or three groups selected from amongC₁-C₄-alkyl, C₁-C₄-alkoxy, halogen or —CF₃,

[0008]  with the proviso that not all the groups R¹, R² and R³ maysimultaneously represent hydrogen,

[0009] optionally in the form of the enantiomers, mixtures ofenantiomers or racemates thereof.

[0010] Preferred are salts of formula 1, wherein

[0011] R¹ and R² which may be identical or different, denote hydrogen,methyl, ethyl, propyl, butyl, methoxy, ethoxy, fluorine, chlorine,bromine, iodine, COOH, OH, —COOmethyl, —CO-methyl, —NH₂, —NH(methyl),—N(methyl)₂, —NH(ethyl), —N(ethyl)₂, —SO₂—OH, —CF₃ or phenyl;

[0012] R³ denotes hydrogen, methyl, ethyl, propyl, butyl, methoxy,ethoxy, fluorine, chlorine, bromine, iodine, —CF₃ or phenyl, while thephenyl ring may optionally be mono-, di- or trisubstituted by one, twoor three groups selected from among methyl, ethyl, propyl, butyl,methoxy, ethoxy, fluorine, chlorine, bromine, iodine or —CF₃,

[0013]  with the proviso that not all the groups R¹, R² and R³ maysimultaneously represent hydrogen,

[0014] optionally in the form of the enantiomers, mixtures ofenantiomers or racemates thereof.

[0015] Particularly preferred are salts of formula 1, wherein

[0016] R¹ and R² which may be identical or different, denote hydrogen,methyl, ethyl, propyl, methoxy, fluorine, chlorine, bromine, iodine,—COOH, OH, —COOmethyl, —CO-methyl, —NH₂, —SO₂—OH or —CF₃;

[0017] R³ denotes hydrogen, methyl, ethyl, methoxy, fluorine, chlorine,—CF₃ or phenyl, while the phenyl ring may optionally be mono- ordisubstituted by one or two groups selected from among fluorine,chlorine, bromine or —CF₃,

[0018]  with the proviso that not all the groups R¹, R² and R³ maysimultaneously represent hydrogen,

[0019] optionally in the form of the enantiomers, mixtures ofenantiomers or racemates thereof.

[0020] Of particular importance according to the invention are compoundsof formula 1 wherein

[0021] R¹ and R² which may be identical or different denote hydrogen,methyl, propyl, methoxy, chlorine, iodine, —COOH, OH, —COOmethyl,—CO-methyl, —NH₂ or —SO₂—OH;

[0022] R³ denotes hydrogen or phenyl, while the phenyl ring mayoptionally be mono- or disubstituted by one or two groups, preferably agroup selected from among fluorine, chlorine, bromine or —CF₃,

[0023]  with the proviso that not all the groups R¹, R² and R³ maysimultaneously represent hydrogen,

[0024] optionally in the form of the enantiomers, mixtures ofenantiomers or racemates thereof.

[0025] Especially preferred according to the invention are compounds ofgeneral formula 1 wherein

[0026] R¹ and R² which may be identical or different, denote hydrogen,methyl, propyl, methoxy, chlorine, iodine, —COOH, OH, —COOmethyl,—CO-methyl, —NH₂ or —SO₂—OH;

[0027] R³ denotes hydrogen,

[0028]  with the proviso that not all the groups R¹, R² and R³ maysimultaneously represent hydrogen,

[0029] optionally in the form of the enantiomers, mixtures ofenantiomers or racemates thereof.

[0030] Also of especial importance according to the invention arecompounds of formula 1 wherein

[0031] R¹ and R² denote hydrogen;

[0032] R³ denotes phenyl, while the phenyl ring may optionally be mono-or disubstituted by one or two groups, preferably a group selected fromamong fluorine, chlorine, bromine or —CF₃, preferably fluorine,

[0033] optionally in the form of the enantiomers, mixtures ofenantiomers or racemates thereof.

[0034] The alkyl groups used, unless otherwise stated, are branched andunbranched alkyl groups having 1 to 4 carbon atoms. Examples include:methyl, ethyl, propyl or butyl. The groups methyl, ethyl, propyl orbutyl may optionally also be referred to by the abbreviations Me, Et,Prop or Bu. Unless otherwise stated, the definitions propyl and butylalso include all possible isomeric forms of the groups in question.Thus, for example, propyl includes n-propyl and iso-propyl, butylincludes iso-butyl, sec. butyl and tert.-butyl, etc.

[0035] The alkyloxy groups used, unless otherwise stated, are branchedand unbranched alkyl groups with 1 to 4 carbon atoms which are linkedvia an oxygen atom. The following may be mentioned, for example:methyloxy, ethyloxy, propyloxy or butyloxy. The groups methyloxy,ethyloxy, propyloxy or butyloxy may optionally also be referred to bythe abbreviations MeO, EtO, PropO or BuO. Unless otherwise stated, thedefinitions propyloxy and butyloxy also include all possible isomericforms of the groups in question. Thus, for example, propyloxy includesn-propyloxy and iso-propyloxy, butyloxy includes iso-butyloxy, sec.butyloxy and tert.-butyloxy, etc. The word alkoxy may also possibly beused within the scope of the present invention instead of the wordalkyloxy. The groups methyloxy, ethyloxy, propyloxy or butyloxy mayoptionally also be referred to as methoxy, ethoxy, propoxy or butoxy.

[0036] Within the scope of the present invention halogen denotesfluorine, chlorine, bromine or iodine. Unless otherwise stated, fluorineand bromine are the preferred halogens. The group CO denotes a carbonylgroup.

[0037] The salts of formula 1 are new acid addition salts of salmeterol,which is known from the prior art. Salmeterol has a chiral centre. Thepresent invention relates to the salts of formula 1 in racemic orenantiomerically pure form. Both the (R)- and the (S)-enantiomer are ofparticular importance. Moreover the present invention relates to thesalts of formula 1 in the form of the non-racemic mixtures of the twoenantiomers.

[0038] In the compounds of general formula 1 the groups R¹, R² and R³,if they do not represent hydrogen, may each be in the ortho, meta orpara position relative to the linking to the carboxyl group. If none ofthe groups R¹, R² and R³ denotes hydrogen, the group R³ is preferablylinked in the meta position and the groups R¹ and R² are linked in theortho and/or para position. If one of the groups R¹, R² and R³ denoteshydrogen, preferably at least one of the other groups is linked in themeta or para position, most preferably in the para position. Compoundswherein the group R³ does not denote hydrogen are of particularimportance according to the invention. In these compounds the group R³is preferably in the meta position, in relation to the carboxyl group.

[0039] The salts 1 according to the invention may be prepared startingfrom the free base of salmeterol analogously to processes known in theart for forming acid addition salts from secondary amines.

[0040] The preparation method comprises reacting the free basesalmeterol with carboxylic acids of formula 2

[0041] wherein the groups R¹, R² and R³ are as hereinbefore defined, insuitable solvents, preferably organic solvents.

[0042] For this purpose the acid 2 is taken up in a suitable solvent,preferably an organic solvent, most preferably a solvent selected fromamong ethyl acetate, methanol, ethanol, iso-propanol and diethylether ormixtures thereof. If desired the abovementioned solvents may also beused in admixture with tert.-butylmethylether or cyclohexane. The acids2 taken up in one of the abovementioned solvents are optionallydissolved with heating, preferably to the boiling temperature of thesolvent. Salmeterol, optionally dissolved in one of the abovementionedsolvents, is added to this solution. The salts 1 are crystallised andisolated from the resulting solution, optionally with cooling.

[0043] As has been found, the compounds of general formula 1 arecharacterised by their range of uses in the therapeutic field.Particular mention should be made of those applications for which thecompounds of formula 1 according to the invention may preferably be usedon the basis of their pharmaceutical activity as betamimetics.

[0044] These include, for example, the treatment of bronchial asthma(normally irritation-induced attacks of bronchial spasm with swelling ofthe mucosa and increased production of mucus), the treatment of COPD(chronic obstructive bronchitis), the inhibition of premature labour andthreatened miscarriage in midwifery (tocolysis), the restoration of thesinus rhythm in the heart in cases of atrio-ventricular block as well asthe correcting of bradycardiac heart rhythm disorders (antiarrhythmicagent), the treatment of circulatory shock (vasodilatation andincreasing the heart-time volume) as well as the treatment of itchingand skin inflammation. The salts of formula 1 are preferably used in thetreatment of asthma or COPD.

[0045] The salts of general formula 1 may be used on their own or inconjunction with other active substances. These may be, in particular,anticholinergics, antiallergics, leukotriene antagonists, dopamineagonists, PDEIV inhibitors and corticosteroids as well as combinationsof active substances.

[0046] Examples of anticholinergics which may be mentioned includeipratropium bromide, oxitropium bromide and particularly tiotropiumbromide. Drug combinations which contain tiotropium bromide as anadditional active substance as well as the compound of formula 1according to the invention are particularly preferred according to theinvention. Combinations which contain, in addition to the compound offormula 1, crystalline tiotropium bromide monohydrate which may beobtained by the experimental procedure described in the experimentalsection are of particular importance.

[0047] This combination is particularly important in the treatment ofasthma or COPD, particularly COPD.

[0048] Within the scope of the present invention, the corticosteroidswhich may optionally be used in conjunction with the compound of formula1 may be compounds selected from among flunisolide, beclomethasone,triamcinolone, budesonide, fluticasone, mometasone, ciclesonide,rofleponide and dexamethasone. Preferably, within the scope of thepresent invention, the corticosteroids are selected from amongflunisolide, beclomethasone, triamcinolone, budesonide, fluticasone,mometasone, ciclesonide and dexamethasone, while budesonide,fluticasone, mometasone and ciclesonide are important and budesonide andfluticasone are particularly important. In some cases, within the scopeof the present patent application, the term steroids is used on its owninstead of the word corticosteroids. Any reference to steroids withinthe scope of the present invention includes a reference to salts orderivatives which may be formed from the steroids. Examples of possiblesalts or derivatives include: sodium salts, sulphobenzoates, phosphates,isonicotinates, acetates, propionates, dihydrogen phosphates,palmitates, pivalates or furoates. In some cases the corticosteroids mayalso occur in the form of their hydrates.

[0049] Within the scope of the present invention, the term dopamineagonists, which may optionally be used in conjunction with the compoundof formula 1, denotes compounds selected from among bromocriptine,cabergolin, alpha-dihydroergocryptine, lisuride, pergolide, pramipexol,roxindol, ropinirol, talipexol, tergurid and viozan. It is preferablewithin the scope of the present invention to use, as combinationpartners with the compound of formula 1, dopamine agonists selected fromamong pramipexol, talipexol and viozan, pramipexol being of particularimportance. Any reference to the abovementioned dopamine agonists alsoincludes, within the scope of the present invention, a reference to anypharmacologically acceptable acid addition salts and hydrates thereofwhich may exist. By the physiologically acceptable acid addition saltsthereof which may be formed by the abovementioned dopamine agonists aremeant, for example, pharmaceutically acceptable salts selected fromamong the salts of hydrochloric acid, hydrobromic acid, sulphuric acid,phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid,succinic acid, lactic acid, citric acid, tartaric acid and maleic acid.

[0050] Examples of antiallergic agents which may be used according tothe invention as a combination with the compound of formula 1 includeepinastin, cetirizin, azelastin, fexofenadin, levocabastin, loratadine,mizolastin, ketotifen, emedastin, dimetinden, clemastine, bamipin,cexchloropheniramine, pheniramine, doxylamine, chlorophenoxamine,dimenhydrinate, diphenhydramine, promethazine, ebastin, desloratidineand meclizine. Preferred antiallergic agents which may be used withinthe scope of the present invention in combination with the compounds offormula 1 according to the invention are selected from among epinastin,cetirizin, azelastin, fexofenadin, levocabastin, loratadine, ebastin,desloratidine and mizolastin, epinastin and desloratidine beingparticularly preferred. Any reference to the above-mentionedantiallergic agents also includes, within the scope of the presentinvention, a reference to any pharmacologically acceptable acid additionsalts thereof which may exist.

[0051] Examples of PDE-IV inhibitors which may be used according to theinvention as a combination with the compound of formula 1 includecompounds selected from among enprofylline, roflumilast, ariflo,Bay-198004, CP-325,366, BY343, D-4396 (Sch-351591), V-11294A andAWD-12-281. Preferred PDE-IV inhibitors are selected from amongenprofylline, roflumilast, ariflo and AWD-12-281. Any reference to theabovementioned PDE-IV inhibitors also includes, within the scope of thepresent invention, a reference to any pharmacologically acceptable acidaddition salts thereof which may exist. By the physiologicallyacceptable acid addition salts which may be formed by the abovementionedPDE-IV inhibitors are meant, for example, pharmaceutically acceptablesalts selected from among the salts of hydrochloric acid, hydrobromicacid, sulphuric acid, phosphoric acid, methanesulphonic acid, aceticacid, fumaric acid, succinic acid, lactic acid, citric acid, tartaricacid and maleic acid. According to the invention, the salts selectedfrom among the acetate, hydrochloride, hydrobromide, sulphate, phosphateand methanesulphonate are preferred.

[0052] Suitable preparations for administering the salts of formula 1include for example tablets, capsules, suppositories and powders, etc.The content of the pharmaceutically active compound(s) should be in therange from 0.05 to 90 wt.-%, preferably 0.1 to 50 wt.-% of thecomposition as a whole. Suitable tablets may be obtained, for example,by mixing the active substance(s) with known excipients, for exampleinert diluents such as calcium carbonate, calcium phosphate or lactose,disintegrants such as corn starch or alginic acid, binders such asstarch or gelatine, lubricants such as magnesium stearate or talc and/oragents for delaying release, such as carboxymethyl cellulose, celluloseacetate phthalate, or polyvinyl acetate. The tablets may also compriseseveral layers.

[0053] Coated tablets may be prepared accordingly by coating coresproduced analogously to the tablets with substances normally used fortablet coatings, for example collidone or shellac, gum arabic, talc,titanium dioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number or layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

[0054] Syrups or elixirs containing the active substances orcombinations thereof according to the invention may additionally containa sweetener such as saccharine, cyclamate, glycerol or sugar and aflavour enhancer, e.g. a flavouring such as vanillin or orange extract.They may also contain suspension adjuvants or thickeners such as sodiumcarboxymethyl cellulose, wetting agents such as, for example,condensation products of fatty alcohols with ethylene oxide, orpreservatives such as p-hydroxybenzoates.

[0055] Capsules containing one or more active substances or combinationsof active substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules.

[0056] Suitable suppositories may be made for example by mixing withcarriers provided for this purpose, such as neutral fats orpolyethyleneglycol or the derivatives thereof. Excipients which may beused include, for example, water, pharmaceutically acceptable organicsolvents such as paraffins (e.g. petroleum fractions), vegetable oils(e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g.ethanol or glycerol), carriers such as e.g. natural mineral powders(e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g.highly dispersed silicic acid and silicates), sugars (e.g. cane sugar,lactose and glucose), emulsifiers (e.g. lignin, spent sulphite liquors,methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g.magnesium stearate, talc, stearic acid and sodium lauryl sulphate).

[0057] The preparations are administered by the usual methods,preferably by inhalation in the treatment of asthma or COPD.

[0058] For inhalation the compounds may be in the form of inhalablepowders, propellant-containing inhalable solutions or suspensions orpropellant-free inhalable solutions or suspensions.

[0059] The inhalable powders which may be used and are preferred withinthe scope of the invention may contain the salts 1 either on their ownor in admixture with suitable physiologically acceptable excipients. Ifthe salts 1 are present in admixture with physiologically acceptableexcipients, the following physiologically acceptable excipients may beused to prepare these inhalable powders according to the invention:monosaccharides (e.g. glucose or arabinose), disaccharides (e.g.lactose, saccharose, maltose), oligo- and polysaccharides (e.g.dextrane), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g.sodium chloride, calcium carbonate) or mixtures of these excipients withone another. Preferably, mono- or disaccharides are used, while the useof lactose or glucose is preferred, particularly, but not exclusively,in the form of their hydrates. For the purposes of the invention,lactose is the particularly preferred excipient, while lactosemonohydrate is most particularly preferred.

[0060] The inhalation aerosols containing propellant gas which may beused according to the invention may contain the salts 1 dissolved in thepropellant gas or in dispersed form. The propellant gases which may beused to prepare the inhalation aerosols are known from the prior art.Suitable propellant gases are selected from among hydrocarbons such asn-propane, n-butane or isobutane and halohydrocarbons such as preferablyfluorinated derivatives of methane, ethane, propane, butane,cyclopropane or cyclobutane. The propellant gases mentioned above may beused on their own or in mixtures thereof. Particularly preferredpropellant gases are fluorinated alkane derivatives selected from TG134a(1,1,1,2-tetrafluoroethane), TG227 (1,1,1,2,3,3,3-heptafluoropropane)and mixtures thereof.

[0061] The propellant-driven inhalation aerosols which may be usedaccording to the invention may also contain other ingredients such asco-solvents, stabilisers, surfactants, antioxidants, lubricants and pHadjusters. All these ingredients are known in the art.

[0062] If the salts 1 according to the invention are administered in theform of propellant-free inhalable solutions and suspensions, the solventused may be an aqueous or alcoholic, preferably an ethanolic solution.The solvent may be water on its own or a mixture of water and ethanol.The relative proportion of ethanol compared with water is not limitedbut the maximum is up to 70 percent by volume, more particularly up to60 percent by volume and most preferably up to 30 percent by volume. Theremainder of the volume is made up of water. The solutions orsuspensions containing 1 are adjusted to a pH of 2 to 7, preferably 2 to5, using suitable acids. The pH may be adjusted using acids selectedfrom inorganic or organic acids. Examples of particularly suitableinorganic acids include hydrochloric acid, hydrobromic acid, nitricacid, sulphuric acid and/or phosphoric acid. Examples of particularlysuitable organic acids include ascorbic acid, citric acid, malic acid,tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid,formic acid and/or propionic acid etc. Preferred inorganic acids arehydrochloric and sulphuric acids. Of the organic acids, ascorbic acid,fumaric acid and citric acid are preferred. If desired, mixtures of theabove acids may be used, particularly in the case of acids which haveother properties in addition to their acidifying qualities, e.g. asflavourings, antioxidants or complexing agents, such as citric acid orascorbic acid, for example. According to the invention, it isparticularly preferred to use hydrochloric acid to adjust the pH.

[0063] For oral administration the tablets may, of course contain, apartfrom the above-mentioned carriers, additives such as sodium citrate,calcium carbonate and dicalcium phosphate together with variousadditives such as starch, preferably potato starch, gelatine and thelike. Moreover, lubricants such as magnesium stearate, sodium laurylsulphate and talc may be used at the same time for the tablettingprocess. In the case of aqueous suspensions the active substances may becombined with various flavour enhancers or colourings in addition to theexcipients mentioned above.

[0064] The dosage of the compounds according to the invention isnaturally highly dependent on the method of administration and thecomplaint which is being treated. When administered by inhalation thecompounds of formula 1 are characterised by a high potency even at dosesin the μg range. The compounds of formula 1 may also be used effectivelyabove the μg range. The dosage may then be in the gram range, forexample.

[0065] The example of synthesis described below serves to illustrate thepresent invention still further. However, it is to be regarded as onlyan example of a procedure, illustrating one possible method of obtainingthe compound according to the invention, without restricting theinvention to the object described below by way of example.

EXAMPLES OF SYNTHESIS

[0066]4-hydroxy-α¹-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-5-(2,4-difluorophenyl)salicylate-salt1a:

[0067] 30 g of salmeterol are dissolved by refluxing in 300 ml of ethylacetate with heating. To this solution are added 18.3 g of5-(2,4-difluorophenyl)salicylic acid (diflunisal). The solution is leftto cool to ambient temperature. The suspension is filtered off, theprecipitate is washed with ethyl acetate and dried in vacuo at 35° C. 46g of the title salt are obtained as a colourless solid.

[0068] Melting point: 104° C.

[0069] The following compounds were prepared analogously:

[0070]4-hydroxy-α¹-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3,5-diisopropyl-salicylate-salt1b;

[0071] Melting point: 115° C.;

[0072]4-hydroxy-α¹-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-4-chloro-salicylate-salt1c;

[0073] Melting point: 123° C.;

[0074]4-hydroxy-α¹-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3,5-dichloro-salicylate-salt1d;

[0075] Melting point: 108° C.;

[0076]4-hydroxy-α¹-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-2,5-dihydroxyterephthalate-salt1e; (base : acid=1:2).

[0077] Melting point: 102° C.;

[0078]4-hydroxy-α¹-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3-methoxysalicylate-salt1f;

[0079] Melting point: 118° C.;

[0080]4-hydroxy-α¹-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-4-methoxysalicylate-salt1g;

[0081] Melting point: 113° C.;

[0082]4-hydroxy-α¹-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-5-methoxysalicylate-salt1h;

[0083] Melting point: 114° C.;

[0084]4-hydroxy-α¹-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-4-methylsalicylate-salt1i;

[0085] Melting point: 116° C.;

[0086]4-hydroxy-α¹-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-5-aminosalicylate-salt1j;

[0087] Melting point: 146° C.;

[0088]4-hydroxy-α¹-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3-chlorosalicylate-salt1k;

[0089] Melting point: 108° C.;

[0090]4-hydroxy-α¹-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-5-sulpho-salicylate-salt1l;

[0091] Melting point: 129° C.;

[0092]4-hydroxy-α¹-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-5-acetylsalicylate-salt1m;

[0093] Melting point: 80° C.;

[0094]4-hydroxy-α¹-[[[6-(4-phenylbutoxy)-hexyl]-amino]-methyl]-1,3-benzenedimethanol-3,5-diiodosalicylate-salt1n;

[0095] Melting point: 133° C.;

[0096] In the abovementioned salts 1 according to the invention the basesalmeterol and the acid of formula 2 are present in a molar ratio ofsalmeterol to acid of 1:1 unless otherwise stated.

[0097] The identity of the abovementioned compounds was confirmed by1H-NMR spectroscopy and ESI mass spectrometry.

[0098] The salts of formula 1 according to the invention may optionallybe used in combination with for example crystalline tiotropium bromidemonohydrate. In so far as the latter is not yet known in the art itspreparation is described hereinafter.

[0099] Tiotropium bromide may be obtained as described in EuropeanPatent Application EP 418 716 A1. Crystalline tiotropium bromidemonohydrate may be obtained therefrom by the following method.

[0100] In a suitable reaction vessel 15.0 kg of tiotropium bromide areadded to 25.7 kg of water. The mixture is heated to 80-90° C. andstirred at constant temperature until a clear solution is formed.Activated charcoal (0.8 kg), moistened with water, is suspended in 4.4kg of water, this mixture is added to the solution containing tiotropiumbromide and rinsed with 4.3 kg of water. The resulting mixture isstirred for at least 15 min at 80-90° C. and then filtered through aheated filter into an apparatus which has been preheated to an outertemperature of 70° C. The filter is rinsed with 8.6 kg of water. Thecontents of the apparatus are cooled to a temperature of 20-25° C. at arate of 3-5° C. per 20 minutes. The apparatus is further cooled to10-15° C. by cold water cooling and the crystallisation is completed bystirring for at least one hour. The crystals are separated off using asuction drier, the isolated crystal slurry is washed with 9 litres ofcold water (10-15° C.) and cold acetone (10-15° C.). The crystalsobtained are dried at 25° C. for 2 hours in a nitrogen current.

[0101] Yield: 13.4 kg of crystalline tiotropium bromide monohydrate (86%of theory).

[0102] The following examples of formulations illustrate the presentinvention without restricting its scope: Examples of pharmaceuticalformulations A) Tablets per tablet active substance  5 mg lactose 140 mgcorn starch 240 mg polyvinylpyrrolidone  10 mg magnesium stearate  5 mg400 mg

[0103] The finely ground active substance, lactose and some of the cornstarch are mixed together. The mixture is screened, then moistened witha solution of polyvinylpyrrolidone in water, kneaded, wet-granulated anddried. The granules, the remaining corn starch and the magnesiumstearate are screened and mixed together. The mixture is compressed toproduce tablets of suitable shape and size. B) Tablets per tablet activesubstance 10 mg lactose 55 mg corn starch 190 mg  microcrystallinecellulose 35 mg polyvinylpyrrolidone 15 mg sodium-carboxymethyl starch23 mg magnesium stearate  2 mg 330 mg 

[0104] The finely ground active substance, some of the corn starch,lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixedtogether, the mixture is screened and worked with the remaining cornstarch and water to form a granulate which is dried and screened. Thesodium carboxymethyl starch and the magnesium stearate are added andmixed in and the mixture is compressed to form tablets of a suitablesize. C) Metering aerosol active substance 0.005 sorbitan trioleate 0.1monofluorotrichloromethane and ad 100 difluorodichloromethane 2:3

[0105] The percentages specified are percent by weight. The suspensionis transferred into a conventional aerosol container with a meteringvalve. Preferably, 50 μl of suspension are delivered per spray. Theactive substance can also be in a higher dose if desired (e.g. 0.02wt.-%). D) Inhalable powder active substance 110 μg lactose monohydratead  25 mg

[0106] The inhalable powder is prepared in the usual way by mixing theindividual ingredients together.

We claim: 1) A compound of Formula 1:

wherein R¹ and R² which may be identical or different, denote hydrogen,C₁-C₄-alkyl, C₁-C₄-alkoxy, halogen, COOH, OH, —COOC₁-C₄-alkyl,—CO-C₁-C₄-alkyl, —NH₂, —NH(C₁-C₄-alkyl), —N(C₁-C₄-alkyl)₂, —SO₂—OH, —CF₃or phenyl; and R³ denotes hydrogen, C₁-C₄-alkyl, C₁-C₄-alkoxy, halogen,—CF₃ or phenyl, wherein the phenyl ring may optionally be mono-, di- ortrisubstituted by one, two or three groups selected from C₁-C₄-alkyl,C₁-C₄-alkoxy, halogen and —CF₃,  with the proviso that the groups R¹, R²and R³ may not all simultaneously represent hydrogen, or an enantiomer,mixture of enantiomers or a racemate thereof. 2) A compound of formula 1according to claim 1, wherein R¹ and R² which may be identical ordifferent, denote hydrogen, methyl, ethyl, propyl, butyl, methoxy,ethoxy, fluorine, chlorine, bromine, iodine, COOH, OH, —COOmethyl,—CO-methyl, —NH₂, —NH(methyl), —N(methyl)₂, —NH(ethyl), —N(ethyl)₂,—SO₂—OH, —CF₃ or phenyl; and R³ denotes hydrogen, methyl, ethyl, propyl,butyl, methoxy, ethoxy, fluorine, chlorine, bromine, iodine, —CF₃ orphenyl, wherein the phenyl ring may optionally be mono-, di- ortrisubstituted by one, two or three groups selected from methyl, ethyl,propyl, butyl, methoxy, ethoxy, fluorine, chlorine, bromine, iodine and—CF₃,  with the proviso that the groups R¹, R² and R³ may not allsimultaneously represent hydrogen, or an enantiomer, mixture ofenantiomers or a racemate thereof. 3) A compounds of formula 1 accordingto claim 1, wherein R¹ and R² which may be identical or different,denote hydrogen, methyl, ethyl, propyl, methoxy, fluorine, chlorine,bromine, iodine, —COOH, OH, —COOmethyl, —CO-methyl, —NH₂, —SO₂—OH or—CF₃; and R³ denotes hydrogen, methyl, ethyl, methoxy, fluorine,chlorine, —CF₃ or phenyl, wherein the phenyl ring may optionally bemono- or disubstituted by one or two groups selected from fluorine,chlorine, bromine or —CF₃,  with the proviso that the groups R¹, R² andR³ may not all simultaneously represent hydrogen, or an enantiomer,mixture of enantiomers or a racemate thereof. 4) A compounds of formula1 according to claim 1, wherein R¹ and R² which may be identical ordifferent denote hydrogen, methyl, propyl, methoxy, chlorine, iodine,—COOH, OH, —COOmethyl, —CO-methyl, —NH₂ or —SO₂—OH; and R³ denoteshydrogen or phenyl, wherein the phenyl ring may optionally be mono- ordisubstituted by one or two groups selected from fluorine, chlorine,bromine and —CF₃,  with the proviso that the groups R¹, R² and R³ maynot all simultaneously represent hydrogen, or an enantiomer, mixture ofenantiomers or a racemate thereof. 5) A compound of formula 1 accordingto claim 1, wherein R¹ and R² which may be identical or different,denote hydrogen, methyl, propyl, methoxy, chlorine, iodine, —COOH, OH,—COOmethyl, —CO-methyl, —NH₂ or —SO₂—OH; and R³ denotes hydrogen,  withthe proviso that the groups R¹, R² and R³ may not all simultaneouslyrepresent hydrogen, or an enantiomer, mixture of enantiomers or aracemate thereof. 6) A compound of formula 1 according to claim 1,wherein R¹ and R² denote hydrogen; and R³ denotes phenyl, wherein thephenyl ring may optionally be mono- or disubstituted by one or twogroups selected from among fluorine, chlorine, bromine and —CF₃, or anenantiomer, mixture of enantiomers or a racemate thereof. 7) A compoundof formula 1 according to claim 6, wherein R³ is a phenyl mono- ordisubstituted by fluorine, or an enantiomer, mixture of enantiomers or aracemate thereof. 8) A pharmaceutical composition comprising a compoundof formula 1 according to claim
 1. 9) A pharmaceutical compositionaccording to claim 8, further comprising at least one additional activesubstance selected from: anticholinergics, antiallergics, leukotrieneantagonists, dopamine antagonists, PDE IV inhibitors andcorticosteroids, or combinations thereof. 10) A pharmaceuticalcomposition according to claim 8, further comprising ipratropiumbromide, oxitropium bromide or tiotropium bromide. 11) A pharmaceuticalcomposition according to claim 8, further comprising tiotropium bromide.12) A pharmaceutical composition according to claim 8, furthercomprising crystalline tiotropium bromide monohydrate. 13) A method oftreating a disease in a patient, wherein said disease is responsive tobetamimetic activity, comprising administering to said patient atherapeutically effective amount of a compound of formula 1 according toclaim
 1. 14) A method of treating asthma or COPD in a patient,comprising administering to said patient a therapeutically effectiveamount of a compound of formula 1 according to claim
 1. 15) A method ofinhibiting premature labor or miscarraige in a patient, restoring thesinus rhythm of the heart in cases of atrio-ventricular block in apatient, correcting a bradycardiac heart rhythm disorder in a patient,or treating circulatory shock, itching or skin inflammation in apatient, comprising administering to said patient a therapeuticallyeffective amount of a compound of formula 1 according to claim 1.